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At least 19 recordsLinked to original sources
PubMed1997

A double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Paroxetine Study Group.

BACKGROUND: 60%-90% of patients with a primary diagnosis of depression also experience symptoms of anxiety, and such patients have a poorer prognosis than those with uncomplicated depression. The serotonin selective reuptake inhibitors have demonstrated efficacy in the treatment of both depression and certain anxiety states. Furthermore, in a metaanalysis of the paroxetine clinical trial database of 2963 patients in whom depression predominated, there was a concomitant reduction in the Hamilton Rating Scale for Depression anxiety factor. The purpose of the present study was to prospectively compare the efficacy of paroxetine and clomipramine in patients specifically selected for coexisting depression and anxiety. METHOD: This was a 12-week, double-blind, parallel-group trial comparing paroxetine 20-40 mg/day with clomipramine 75-150 mg/day in 1002 patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Clinical Anxiety Score (CAS) > or = 11 after a 3-7 day placebo run-in period. RESULTS: Both paroxetine and clomipramine reduced the MADRS and CAS ratings at 2, 6, and 12 weeks and at endpoint, with no significant differences between treatment groups at any time point. CGI severity of illness and global improvement ratings were also similar throughout the trial; however, there was a statistically significant difference in the CGI efficacy index at 6 weeks and at endpoint, favoring paroxetine (p = .015 and p = .015, respectively). Paroxetine resulted in fewer treatment-emergent adverse experiences and related withdrawals than clomipramine (p = .025 and p = .008, respectively). The number of serious adverse experiences was not significantly different in the paroxetine group compared with the clomipramine group (14 [2.8%] vs. 27 [5.4%]), but did approach statistical significance (p = .056). Anticholinergic-emergent adverse experiences were reported twice as frequently by patients in the clomipramine group as in the paroxetine group (36.1% vs. 18.6%). CONCLUSION: There was no evidence of any significant difference in efficacy between paroxetine and clomipramine in patients with coexisting depression and anxiety. However, paroxetine was better tolerated as shown by total treatment-emergent adverse experiences, anticholinergic adverse experiences, and withdrawals due to adverse experiences.

Adolescent↗
PubMed1997

Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators.

Paroxetine has been shown to be effective in panic disorder in three 10- to 12-week studies. This trial studied the longer term effects of paroxetine in patients with DSM-III-R defined panic disorder. Patients who satisfactorily completed a 12-week, double-blind, placebo-controlled study of paroxetine and clomipramine could choose to continue receiving their randomized treatment for a further 36 weeks. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. In total, 176 patients were included in the intention-to-treat population. The number of full panic attacks decreased in all three groups during the 12-week study, and improvements continued with long-term therapy. Paroxetine was statistically significantly more effective than placebo throughout the long-term study with respect to reduction from baseline of full panic attacks, and at the end of treatment with respect to the proportion of patients who eventually experienced no panic attacks. There were no significant differences between paroxetine and clomipramine. The proportion of patients who withdrew from the study due to adverse effects was greater in the clomipramine group (19%) than in either the paroxetine group (7%) or the placebo group (9%). Paroxetine was significantly more effective than placebo and as effective as (but better tolerated than) clomipramine in the long-term treatment of panic disorder. Not only was efficacy maintained, but continued improvement was also seen, indicating the importance of long-term treatment in patients with panic disorder.

Adolescent↗
PubMed1997

A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators.

The aim of this 12-week, double-blind, parallel group, placebo-controlled study was to compare paroxetine with clomipramine in 367 patients with DSM-III-R defined panic disorder. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. Paroxetine produced significant improvements compared with placebo in various measurements of panic attack frequency, and was as effective as clomipramine. However, paroxetine appeared to have a more rapid onset of action than clomipramine in reducing the number of panic attacks to zero. There was an equivalent improvement with both paroxetine and clomipramine in the supportive efficacy variables which assessed associated aspects of therapeutic improvement. Significantly more adverse effects were reported in the clomipramine group compared with the paroxetine group, while there was no difference between the paroxetine and placebo groups.

Adolescent↗
PubMed1998

One year real world prospective follow-up study of a major depressive episode of patients treated with paroxetine and pindolol or paroxetine for 6 weeks.

The objective of our study was an assessment of outcome in a 1 year 'real world', prospective follow-up study of patients who were treated with paroxetine 20 mg plus pindolol 7.5 mg or paroxetine 20 mg plus placebo for 6 weeks. Eighty patients recruited to a double-blind placebo-controlled randomized 6 weeks study of paroxetine and pindolol were followed up for 6 months and interviewed after 1 year. A Kaplan-Meier survival analysis of the patients who relapsed having taken paroxetine and pindolol, compared with those who relapsed having taken paroxetine and placebo, shows that the pindolol group had a better clinical outcome. After 1 year patients who had responded to medication by 2 weeks had done better than the rest and they had been more compliant with medication for 6 months. There are indications that the earlier a patient responds to medication, the better the long-term outcome.

Adult↗
PubMed1996

Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. OCD Paroxetine Study Investigators.

BACKGROUND: The aim was to assess the effect of a flexible dose of paroxetine, compared with clomipramine and placebo, in obsessive-compulsive disorder (OCD). METHOD: In a multinational randomised study, 406 subjects with OCD of at least six months duration received double-blind medication for up to 12 weeks. Doses were adjusted according to therapeutic effect and side-effects. Primary efficacy measures were the Yale-Brown Obsessive-Compulsive Scale and the National Institute of Mental Health Obsessive-Compulsive Scale. Secondary efficacy measures were the Montgomery-Asberg Depression Rating Scale, Symptom Check-List (90), Clinical Global Impression, and Patients Global Evaluation. RESULTS: Paroxetine was significantly more effective than placebo, and of comparable efficacy to clomipramine. Paroxetine had significantly superior tolerability to clomipramine on three measures: CGI efficacy index, anticholinergic adverse events, and adverse events leading to withdrawal. CONCLUSION: Paroxetine is as effective as clomipramine in the treatment of OCD. The comparable efficacy and better tolerability of paroxetine suggest that it would be an appropriate treatment for OCD.

Adolescent↗
PubMed1992

A double-blind multicentre study of paroxetine and amitriptyline in depressed outpatients. Italian Paroxetine Study Group.

A comparative double-blind study of paroxetine and amitriptyline in the treatment of depressed hospital outpatients was undertaken at 15 centres in Italy. Three hundred and nine patients of either sex were admitted to the study. The starting dose of paroxetine was 20 mg daily and of amitriptyline 75 mg daily in divided doses; at week 3 these doses could be increased at the investigators' discretion. Efficacy was measured on the Hamilton Depression Rating Scale and on Clinical Global Impression. Both treatment groups showed significant improvement at week 6 with no significant between-group differences. Significantly fewer patients receiving paroxetine reported adverse events compared with those on amitriptyline (44% vs 62%; p < 0.01 in favour of paroxetine).

Adult↗
PubMed1998

Paroxetine. An update of its pharmacology and therapeutic use in depression and a review of its use in other disorders.

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT), which was previously reviewed as an antidepressant in Drugs in 1991. Since then, more comparative trials with other antidepressants have become available, and its use in the elderly and as long term maintenance therapy has been investigated. Paroxetine has also been studied in several other disorders with a presumed serotonergic component, primarily obsessive compulsive disorder (OCD) and panic disorder. In short term clinical trials in patients with depression, paroxetine produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with other agents including tricyclic antidepressants (TCAs), maprotiline, nefazodone and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline. Long term data suggest that paroxetine is effective in preventing relapse or recurrence of depression in patients treated for up to 1 year. In the elderly, the overall efficacy of paroxetine was at least as good as that of comparator agents. In short term clinical trials involving patients with OCD or panic disorder, paroxetine was significantly more effective than placebo and of similar efficacy to clomipramine. Limited long term data show that paroxetine is effective in maintaining a therapeutic response over periods of 1 year (OCD) and up to 6 months (panic disorder). Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache. Like the other SSRIs, paroxetine is better tolerated than the TCAs, causing few anticholinergic adverse effects. The most commonly reported adverse event associated with paroxetine treatment is nausea, although this is generally mild and subsides with continued use. Fewer withdrawals from treatment due to adverse effects occurred with paroxetine treatment than with TCAs. The adverse events profile of paroxetine appears to be broadly similar to that of other SSRIs, although data from comparative trials are limited. Serious adverse effects associated with paroxetine are very rare. In conclusion, paroxetine is effective and well tolerated, and suitable as first-line therapy for depression. It also appears to be a useful alternative to other available agents for the treatment of patients with OCD or panic disorder.

Antidepressive Agents, Second-Generation↗
PubMed1998

Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo.

Major depression may require antidepressant treatment for several years. This necessitates consideration of the long-term effects of antidepressants on multiple clinical endpoints. The antidepressants paroxetine and fluvoxamine are potent in vitro inhibitors of CYP2D6 and CYP1A2 isozymes, respectively. CYP2D6 and CYP1A2 are important for the clearance of 30 or more frequently used medications. Moreover, CYP1A2 also contributes to metabolism of 17beta-estradiol and metabolic activation of environmental procarcinogens (e.g., arylamines in cigarette smoke). The aim of this study was to assess the determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition during paroxetine and fluvoxamine treatment. Healthy volunteers and patients received caffeine (100 mg) and dextromethorphan (30 mg) at baseline and at steady state of paroxetine (10-20 mg/day, 5-74 days, N = 13) or fluvoxamine (50-100 mg/day, 5-43 days, N = 8). The caffeine metabolic ratio (CMR) and the log O-demethylation ratio (ODMR) of dextromethorphan in overnight urine were used as in vivo indices of the CYP1A2 and CYP2D6 isozyme activities, respectively. All subjects had an extensive metabolizer phenotype for CYP2D6. After fluvoxamine treatment, baseline CMR 5.1 +/- 1.4 (mean +/- SD) decreased to 2.7 +/- 1.1 (p < 0.01). Paroxetine did not have a significant effect on CMR (p > 0.05). In seven of eight subjects in the fluvoxamine group, posttreatment CMR was comparable with the minimum CMR value (2.0) attainable in nonsmoking healthy volunteers. After paroxetine treatment, log ODMR changed from a baseline value of -2.28 +/- 0.37 to -1.13 +/- 0.44, indicating significant inhibition of CYP2D6 (p < 0.001). Subjects' CYP2D6 phenotype did not change after paroxetine treatment. Fluvoxamine had no significant effect on log ODMR (p > 0.05). The extent of inhibition of CYP2D6 and CYP1A2 by paroxetine and fluvoxamine, respectively, displayed a positive correlation with baseline enzyme activity (p < 0.05). In addition, a negative association was found between the plasma paroxetine concentration and the CYP2D6 activity after paroxetine treatment (r = -0.47, p < 0.05). These data indicate that paroxetine and fluvoxamine treatment with minimum clinically effective doses significantly inhibit CYP2D6 and CYP1A2, respectively. The extent of inhibition of CYP2D6 by paroxetine and of CYP1A2 by fluvoxamine is dependent in part on the baseline enzyme activity. The interindividual variability in CYP2D6 inhibition by paroxetine can also be explained by variability in plasma paroxetine concentration. Most patients treated with fluvoxamine (50-100 mg/day) will reach population minimums for CYP1A2 activity. These results have potential implications for interindividual variability in the risk for drug-drug interactions mediated by CYP2D6 and CYP1A2 as well as for the disposition of 17beta-estradiol and environmental procarcinogens.

Adult↗
PubMed1998

A post hoc comparison of paroxetine and nortriptyline for symptoms of traumatic grief.

BACKGROUND: This report presents the results of an open-trial pilot study of paroxetine for symptoms of traumatic grief, compared with the effects of nortriptyline in an archival contrast group. METHOD: Data are presented on 15 subjects (4 men, 11 women), ranging in age from 40 to 79 years (mean age = 57 years), who experienced the loss of a spouse (N = 8), child (N =5), grandchild (N = 1), or parent (N = 1). Subjects were required to have a baseline score on the Inventory of Complicated Grief (ICG) of > or = 20. Treatment with paroxetine began at a median of 17 months (range, 6-139 months) after the loss. Paroxetine-treated subjects received a psychotherapy tailored for traumatic grief. Depressive symptoms were assessed by using the Hamilton Rating Scale for Depression (HAM-D). The ICG and the HAM-D were administered weekly over 4 months of paroxetine treatment (median dose = 30 mg/day). The group receiving paroxetine were then compared with a group (N = 22) participating in a separate trial of nortriptyline (median dose = 77.5 mg/day) for treatment of bereavement-related major depressive episodes. RESULTS: Level of traumatic grief symptoms (ICG) decreased by 53%, and depression ratings (HAM-D) decreased by 54% in paroxetine-treated subjects. Nortriptyline showed clinical effects comparable to those of paroxetine. CONCLUSION: Paroxetine may be an effective agent in the treatment of traumatic grief symptoms. A comparison of the paroxetine-treated group with a nortriptyline-treated group suggests that both agents have comparably beneficial effects on the symptoms of traumatic grief (as well as those of depression). However, the higher rate of diagnostic comorbidity in the paroxetine-treated group, together with the greater chronicity of their symptoms and the greater safety of paroxetine in overdose, leads us to favor paroxetine over nortriptyline for traumatic grief symptoms in general psychiatric practice. Further controlled evaluation of paroxetine for traumatic grief is necessary.

Adjustment Disorders↗
PubMed1990

Paroxetine as an in vivo indicator of 3,4-methylenedioxymethamphetamine neurotoxicity: a presynaptic serotonergic positron emission tomography ligand?

The present study sought to determine whether [3H]paroxetine, a potent and selective inhibitor of serotonin uptake in vitro, could be used to label the serotonin transporter in the rat brain in vivo such that it might be employed to develop a presynaptic serotonergic positron emission tomography ligand. Tritium labeled paroxetine was administered intravenously to rats by means of tail vein injection. Four hours later, specific [3H]paroxetine binding was determined by subtracting non-specific binding in the cerebellum from total binding in other brain regions of interest. The distribution of specific [3H]paroxetine binding paralleled the distribution of serotonin uptake sites in all brain regions examined. Pretreatment with serotonin re-uptake inhibitors (citalopram or sertraline) reduced in vivo specific [3H]paroxetine binding by as much as 99%. Specific in vivo [3H]paroxetine binding was further characterized through the use of 5,7-dihydroxytryptamine (5,7-DHT), a known serotonergic neurotoxin. 5,7-DHT (200 micrograms, i.c.v.) caused a marked reduction in specific [3H]paroxetine binding, and induced a prolonged depletion of regional brain serotonin. In a final study, the feasibility of using in vivo [3H]paroxetine binding as an indicator of serotonergic damage induced by another neurotoxin (3,4-methylenedioxymethamphetamine, MDMA) was tested. MDMA-treated rats showed a profound reduction in in vivo [3H]paroxetine binding, along with a lasting depletion of regional brain serotonin. These results demonstrate that [3H]paroxetine can be used to label serotonin uptake sites in the rat brain in vivo, and that the damage induced by serotonergic neurotoxins can be detected using in vivo [3H]paroxetine binding as an indicator. Paroxetine (or one of its derivatives) therefore holds promise as a PET ligand for studying serotonergic neurons in the living human brain in health as well as after neurotoxic injury.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Immunological studies on paroxetine, a novel anti-depressant drug.

Paroxetine is a novel and selective neuronal 5-hydroxy-tryptamine uptake inhibitor with anti-depressant activity. Paroxetine was examined for its ability to induce adverse immunological reactions, either as a consequence of a specific immune response or by a direct or indirect effect on the immune system. Paroxetine did not react in vitro with protein amino or thiol groups, suggesting that it lacks the capacity to form potentially immunogenic hapten protein conjugates. No anti-paroxetine antibody was detected in plasma or serum samples from patients and rats following oral administration over prolonged periods, or from epicutaneously exposed guinea pigs, or from rabbits given paroxetine in Freund's adjuvant, suggesting that paroxetine does not have the capacity to elicit humoral immune responses. Guinea pigs epicutaneously exposed to paroxetine did not develop contact sensitivity, suggesting that it does not have the capacity to elicit cell-mediated immune responses. These results suggest that paroxetine lacks intrinsic immunogenicity. Anti-SRBC antibody plaque-forming cell responses in mice were unaffected by oral administration of paroxetine, and paroxetine had no significant effect on ex vivo and in vitro murine macrophage phagocytosis of opsonized SRBC or on ex vivo murine splenocyte mitogen responses, suggesting that paroxetine does not exert modulatory effects on the immune system or on macrophage function. These findings, together with the results of pre-clinical safety evaluation studies, suggest that paroxetine is unlikely to have immunotoxic effects.

Adult↗
PubMed1993

Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine.

Nine extensive metabolizers (EMs) and eight poor metabolizers (PMs) of sparteine took a single oral dose of 100 mg of desipramine HCI before and while taking paroxetine 20 mg per day. Before paroxetine, the median of the total desipramine clearance was 7 times higher in EMs than in PMs (102 and 15 l.h-1 respectively). This confirms that desipramine is extensively metabolized via the sparteine/debrisoquine oxidation polymorphism i.e. by CYP2D6. During paroxetine, the median clearances were 22 l.h-1 and 18 l.h-1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l.h-1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l.h-1 respectively). The increase in this clearance in PMs suggests that paroxetine is an inducer of the alternative, unidentified P450(s) which catalyze(s) the formation of 2-OH-desipramine in this phenotype. Before paroxetine, the median amounts of 2-OH-desipramine glucuronide recovered in urine were 69% and 68% of the total recovery of 2-OH-desipramine in urine in EMs and PMs respectively. During paroxetine, the corresponding values were 77% and 84%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1998

Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline.

Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT < or = 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients had IELTs of more than 1 minute (group 2). The geometric mean IELT was 14 seconds in group 1 and 83 seconds in group 2. Twelve patients in group 1 and five in group 2 were randomized to the paroxetine 20 mg/day. The percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% (95% confidence interval [CI], 216-758%) in group 1 and 480% (95% CI, 177-1,118%) in group 2 (p = 0.81). After 6 weeks of treatment with paroxetine, the geometric mean IELT was 92 seconds in group 1 and 602 seconds in group 2 (p < 0.001). Therefore, the paroxetine-induced percentage increase in IELT seems to be independent of the baseline IELT. This suggests that ejaculation-delaying side effects of some SSRIs investigated in men with lifelong rapid ejaculation may be generalized to men with less-rapid ejaculation.

Adolescent↗
PubMed1989

A review of the metabolism and pharmacokinetics of paroxetine in man.

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to the clinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokinetic parameters are not predictable from single-dose data. In many subjects, daily administration of 20-50 mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30 mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single dose. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events).

Antidepressive Agents↗
PubMed1989

[Behavioral pharmacological properties of the novel antidepressant paroxetine, a selective 5-HT uptake inhibitor].

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

Aggression↗
PubMed1998

A double-blind comparison of the efficacy and safely of paroxetine and imipramine in the treatment of depression with dementia.

OBJECTIVES: To compare the efficacy of paroxetine and imipramine prospectively in patients with coexisting depression and dementia. METHODS: An 8-week, double-blind, parallel group trial comparing paroxetine 20-40 mg/day with imipramine 50-100 mg/day in 198 patients aged 60 years or over with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Folstein mini-mental state evaluation score of 17-23 points after a 3- to 7-day placebo run-in period. RESULTS: Both paroxetine and imipramine reduced the MADRS and the Clinical Global Impression (CGI) severity-of-illness and global improvement scores at weeks 2, 4, 8 and at endpoint, with no significant differences between treatment groups at any timepoint (MADRS, p > or = 0.368; cgi, p > or = 0.286). There was a statistically significant difference in favour of paroxetine at both the week 4 and week 8 timepoints (analysis of variance, p < or = 0.049) in the Cornell scale for depression in dementia: at endpoint there was no significant difference between treatments (p = 0.103). Treatment-emergent adverse experiences were reported by 51.5% (51/99) of patients treated with paroxetine and 50.5% (50/99) of patients treated with imipramine. Anticholinergic adverse experiences (paroxetine 6.1%; imipramine 13.1%) and serious non-fatal adverse experiences (paroxetine 4.0%; imipramine 8.1%) were reported by more patients in the imipramine group than in the paroxetine group. CONCLUSIONS: Paroxetine and imipramine were both effective in the treatment of depression in elderly subjects with co-existing dementia, and no significant differences were detected between the groups. There were trends suggesting that paroxetine was better tolerated than imipramine in terms of anticholinergic adverse experiences and serious non-fatal adverse experiences.

Aged↗
PubMed1987

Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain.

Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.

Animals↗
PubMed1997

How long should pindolol be associated with paroxetine to improve the antidepressant response?

A double-blind study was undertaken to investigate the period of treatment with the beta-adrenoreceptor/5-hydroxytryptamine 1A (5-HT1A) antagonist pindolol required to enhance the antidepressant effects of paroxetine. After 1 week of a placebo run-in period, 63 untreated major depressive inpatients were randomly assigned to three different groups. Group 1 received paroxetine (20 mg/day) plus placebo (4 weeks). Group 2 received paroxetine (20 mg/day) plus pindolol (7.5 mg/day) for 1 week and placebo for 3 weeks. Group 3 received both active treatments for the entire duration of the study (4 weeks). Clinical response was defined as a reduction of the score in the Hamilton Rating Scale for Depression (HAM-D) to 8 or below. Also, to preliminarily examine whether beta-adrenoreceptor blockade was involved in the action of pindolol, another group of 10 inpatients was treated in an open-label manner with paroxetine (20 mg/day) plus 50 mg/day of the beta-adrenergic antagonist metoprolol, devoid of significant affinity for 5-HT1A receptors. At endpoint, the incidence of treatment-emergent side effects did not significantly differ among the three groups. After 1 and 2 weeks of treatment, the two groups treated with paroxetine plus pindolol displayed a significantly greater response rate than the group treated with paroxetine plus placebo. At study completion, only the patients treated with pindolol for the entire period showed a significantly greater response rate (p = 0.05). HAM-D score were also significantly lower at endpoint in patients treated with the combination for 4 weeks (p = 0.00003). The group of patients treated with paroxetine and metoprolol exhibited a side-effect profile comparable to that of paroxetine alone. Response rates were also comparable. These findings support the efficacy of pindolol, but not of metoprolol, in accelerating the antidepressant effect of paroxetine and suggest that the administration of pindolol for the entire period of the acute treatment may increase the efficacy of paroxetine.

Adrenergic beta-Antagonists↗